A-Band Titin Truncation in Zebrafish Causes Dilated Cardiomyopathy and Hemodynamic Stress Intolerance

Huttner, Inken G.; Wang, Louis W.; Santiago, Celine; Horvat, Claire; Johnson, Renée; Cheng, Delfine; Frieling-Salewsky, Marion von; Hillcoat, Karen; Bemand, Timothy; Trivedi, Gunjan; Braet, Filip; Hesselson, Daniel; Alford, Kevin; Hayward, Christopher; Seidman, Jonathan G.; Seidman, Christine E.; Feneley, Michael P.; Linke, Wolfgang A.; Fatkin, Diane

doi:10.1161/circgen.118.002135

Cited by 44 publications

(50 citation statements)

References 35 publications

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“…= not assessed. [1] ( Kaartinen et al, 1995 ); [2] ( Li et al, 1996 ; Capetanaki et al, 1997 ); [3] ( Takeshima et al, 1998 ); [4] ( Chu et al, 1998 ); [5] ( Mills et al, 1999 ); [6] ( Sullivan et al, 1999 ; Nikolova et al, 2004 ); [7] ( Ferreira-Cornwell et al, 2002 ); [8] ( Kostetskii et al, 2005 ; Li et al, 2005 ); [9] ( Dalkilic et al, 2006 ); [10] ( White et al, 2006 ; Quang et al, 2015 ); [11] ( Haghighi et al, 2006 ); [12] ( Liu et al, 2006 ); [13] ( Kannankeril et al, 2006 ); [14] ( Bendig et al, 2006 ; Pott et al, 2018 ); [15] ( Katsuno et al, 2008 ); [16] ( Kostareva et al, 2008 ); [17] ( Gramlich et al, 2009 ); [18] ( Zheng et al, 2009 ); [19] ( Vogel et al, 2009 ); [20] ( Li et al, 2010 ); [21] ( Chopra et al, 2010 ); [22] ( Watanabe et al, 2011 ); [23] ( Koshimizu et al, 2011 ); [24] ( Guo et al, 2012 ); [25] ( Li et al, 2012 ); [26] ( Shan et al, 2012 ); [27] ( Bround et al, 2012 ); [28] ( Haghighi et al, 2012 ) [29] ( Huttner et al, 2013 ); [30] ( Clemen et al, 2015 ; Stockigt et al, 2020 ); [31] ( Tapia et al, 2015 ); [32] ( Glynn et al, 2015 ); [33] ( Zou et al, 2015 ); [34] ( Wan et al, 2016 ); [35] ( Khan et al, 2016 ; van den Hoogenhof et al, 2018 ); [36] ( Shih et al, 2016 ); [37] ( Begay et al, 2018 ); [38] ( Murayama et al, 2018 ); [39] ( Stroud et al, 2018 ); [40] ( Huttner et al, 2018 ); [41] ( Padron-Barthe et al, 2019 ); [42] ( Zheng et al, 2019 ); [43] ( Brodehl et al, 2019d ); [44] (…”

Section: Animal Models For Acm Associated With Mutations In Nondesmosmentioning

confidence: 99%

Genetic Animal Models for Arrhythmogenic Cardiomyopathy

Gerull

Brodehl

2020

Front. Physiol.

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Arrhythmogenic cardiomyopathy has been clinically defined since the 1980s and causes right or biventricular cardiomyopathy associated with ventricular arrhythmia. Although it is a rare cardiac disease, it is responsible for a significant proportion of sudden cardiac deaths, especially in athletes. The majority of patients with arrhythmogenic cardiomyopathy carry one or more genetic variants in desmosomal genes. In the 1990s, several knockout mouse models of genes encoding for desmosomal proteins involved in cell–cell adhesion revealed for the first time embryonic lethality due to cardiac defects. Influenced by these initial discoveries in mice, arrhythmogenic cardiomyopathy received an increasing interest in human cardiovascular genetics, leading to the discovery of mutations initially in desmosomal genes and later on in more than 25 different genes. Of note, even in the clinic, routine genetic diagnostics are important for risk prediction of patients and their relatives with arrhythmogenic cardiomyopathy. Based on improvements in genetic animal engineering, different transgenic, knock-in, or cardiac-specific knockout animal models for desmosomal and nondesmosomal proteins have been generated, leading to important discoveries in this field. Here, we present an overview about the existing animal models of arrhythmogenic cardiomyopathy with a focus on the underlying pathomechanism and its importance for understanding of this disease. Prospectively, novel mechanistic insights gained from the whole animal, organ, tissue, cellular, and molecular levels will lead to the development of efficient personalized therapies for treatment of arrhythmogenic cardiomyopathy.

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Section: Animal Models For Acm Associated With Mutations In Nondesmosmentioning

confidence: 99%

Genetic Animal Models for Arrhythmogenic Cardiomyopathy

Gerull

Brodehl

2020

Front. Physiol.

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“…Further elucidation of these pathways is required to better understand how TTNtv lead to DCM phenotypes which will provide additional opportunities to develop therapies. Animal models are essential for understanding molecular pathways, and several have been utilized to study TTNtv including a mouse model with an A-band truncation mutation, and zebrafish models that have several different truncation variations [ 39 , 40 , 41 , 42 ]. A review of these important models has been recently carried out [ 43 ].…”

Section: Truncation Mutations In Ttn Cause Dilamentioning

confidence: 99%

Modifications of Titin Contribute to the Progression of Cardiomyopathy and Represent a Therapeutic Target for Treatment of Heart Failure

Tharp

Mestroni

Taylor

2020

JCM

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Titin is the largest human protein and an essential component of the cardiac sarcomere. With multiple immunoglobulin(Ig)-like domains that serve as molecular springs, titin contributes significantly to the passive tension, systolic function, and diastolic function of the heart. Mutations leading to early termination of titin are the most common genetic cause of dilated cardiomyopathy. Modifications of titin, which change protein length, and relative stiffness affect resting tension of the ventricle and are associated with acquired forms of heart failure. Transcriptional and post-translational changes that increase titin’s length and extensibility, making the sarcomere longer and softer, are associated with systolic dysfunction and left ventricular dilation. Modifications of titin that decrease its length and extensibility, making the sarcomere shorter and stiffer, are associated with diastolic dysfunction in animal models. There has been significant progress in understanding the mechanisms by which titin is modified. As molecular pathways that modify titin’s mechanical properties are elucidated, they represent therapeutic targets for treatment of both systolic and diastolic dysfunction. In this article, we review titin’s contribution to normal cardiac physiology, the pathophysiology of titin truncation variations leading to dilated cardiomyopathy, and transcriptional and post-translational modifications of titin. Emphasis is on how modification of titin can be utilized as a therapeutic target for treatment of heart failure.

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“…In order to test the power of multiple imaging techniques to detect subtle adult phenotypes, we first needed to select a suitable model. Many homozygous mutant zebrafish exhibiting cardiac defects at early developmental stages have been reported (Sehnert et al, 2002;Miura et al, 2011;Tu et al, 2012;Wilkinson et al, 2014;Grant et al, 2017), and some animals heterozygous for mutations display subtle defects in adult stages (Ahlberg et al, 2018;Huttner et al, 2018). Other zebrafish mutants do not display embryonic phenotypes but exhibit pericardial edema at adult stages (Guerra et al, 2018), indicating cardiac function defects.…”

Section: Selecting a Mutant To Test The Sensitivity Of Our Imaging Plmentioning

confidence: 99%

Integration of multiple imaging platforms to uncover cardiac defects in adult zebrafish

Bensimon-Brito

Boezio

Cardeira-da-Silva

et al. 2020

Preprint

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Mammalian models have been instrumental to investigate adult heart function and human disease. However, electrophysiological differences with human hearts and high costs emphasize the need for additional models. The zebrafish is a well-established genetic model to study cardiac development and function; however, analysis of cardiac phenotypes in adult specimens is particularly challenging as they are opaque. Here, we optimized and combined multiple imaging techniques including echocardiography, magnetic resonance imaging and micro-computed tomography to identify and analyze cardiac phenotypes in adult zebrafish. Using alk5a/tgfbr1a mutants as a case study, we observed morphological and functional cardiac defects, which were undetected with conventional approaches. Correlation analysis of multiple parameters revealed an association between hemodynamic defects and structural alterations of the heart, as observed clinically. Thus, we report a comprehensive and sensitive platform to identify otherwise indiscernible cardiac phenotypes in adult zebrafish, a model with clear advantages to study cardiac function and disease.

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A-Band Titin Truncation in Zebrafish Causes Dilated Cardiomyopathy and Hemodynamic Stress Intolerance

Cited by 44 publications

References 35 publications

Genetic Animal Models for Arrhythmogenic Cardiomyopathy

Genetic Animal Models for Arrhythmogenic Cardiomyopathy

Modifications of Titin Contribute to the Progression of Cardiomyopathy and Represent a Therapeutic Target for Treatment of Heart Failure

Integration of multiple imaging platforms to uncover cardiac defects in adult zebrafish

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